Marijuana (MJ) use is prevalent, and has serious public health consequences, including a fast progression to dependence and a greater likelihood of engaging in other risky behaviors. This is of particular importance to women, who comprise a growing proportion of MJ smokers and are more likely to relapse than men. Treatment options for MJ smokers are currently limited and improved understanding of mechanisms that may trigger MJ use and the transition from MJ use to dependence is critical. The overarching goal of this grant proposal is to elucidate sex differences in processes mediating MJ use in non-treatment seeking, non-dependent regular users of MJ~ a group who is at great risk for developing MJ dependence. Therefore, in male and female MJ smokers, we will measure 1) the response to stress, a factor often implicated in drug abuse, using a standardized psychological stressor, and 2) stress-induced MJ self-administration. As a proof-of-concept approach we will administer intranasal (i.n.) oxytocin to test whether oxytocin, a hormone linked to the inhibition of stress response and potentially more effective in women, decreases stress and stress-induced MJ self-administration. Specifically, in MJ smokers, we will determine (1) sex differences in the behavioral and physiological stress response (Aim 1a) and subsequent MJ self-administration (Aim 1b) after exposure to a social stressor (Trier Social Stress Test~ TSST) compared to a stress-free (No Stress Test~ NST) condition through use of a naturalistic MJ self-administration paradigm~ and (2) the effects of i.n. oxytocin administratio compared with placebo on the behavioral response to TSST vs. NST (Aim 2a) and subsequent MJ self-administration (Aim 2b) in males compared to females (Aim 2c). Findings from this project will provide critical information for this particularly at-risk group of MJ smokers to bettr inform development of sex-specific interventions. Oxytocin administration, if effective in mitigating the behavioral response to stress, would strongly support our proposed mechanistic hypothesis and would support further exploration of possible intervention techniques for stress-induced MJ use. Results from this investigation will also lay critical groundwork for further research of behavioral and mechanistic factors underlying the continued use of MJ and the progression to dependence in MJ users, as well as users of other drugs of abuse.